Hypoxic‑ischemic encephalopathy is one of the most notable causes of brain injury in newborns. Cerebral ischemia and reperfusion lead to neuronal damage and neurological disability. In vitro and in vivo analyses have indicated that E3 ubiquitin protein ligase (Huwe1) is important for the process of neurogenesis during brain development; however, the exact biological function and the underlying mechanism of Huwe1 remain controversial. In the present study, neural progenitor cells, L2.3, of which we previously generated from rat E14.5 cortex, were used to investigate the role of Huwe1 and its effects on the downstream N‑Myc‑Delta‑like 3‑Notch1 signaling pathway during oxygen‑glucose deprivation (OGD). To evaluate the role of Huwe1 in L2.3 cells, transduction, cell viability, lactate dehydrogenase, 5‑bromo‑2'deoxyurine incorporation, western blotting and immunocytochemical assays were performed. The results of the present study indicated that Huwe1 rescued L2.3 cells from OGD‑induced insults by inhibiting proliferation and inducing neuronal differentiation. In addition, Huwe1 was suggested to mediate the survival of L2.3 cells by inhibiting the activation of the N‑Myc‑Notch1 signaling pathway. Of note, the effects of Huwe1 on Notch1 signaling were completely abolished by knockdown of N‑Myc, indicating that Huwe1 may require N‑Myc to suppress the activation of the Notch1 signaling in L2.3 cells. The determination of the neuroprotective function of the Huwe1‑N‑Myc‑Notch1 axis may provide insight into novel potential therapeutic targets for the treatment of ischemic stroke.